Aminoacyl aminosteroids



United States Patent 3,196,169 AMINOACYL AMINOSTEROES Harvey E. Album,West Chester, and Norman H. Grant,

Wynnewood, Pa., assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware N0 Drawing. Filed Nov. 3, 1964,Ser. No. 408,679 11 Claims. (Cl. 260-3973) This application is acontinuation-in-part of copending application Serial No. 345,574, filedFebruary 18, 1964, now abandoned.

This invention is directed to novel aminosteroids and more particularlyto 3a-(carboxamido)-5ot-pregnan-20 ones and3tx-(carboxamido)-5a-pregnan-20-ols and to the method by which these newsteroids are prepared.

The new compounds of the present invention considered in their broadestaspect include those encompassed within the following structuralformula:

wherein R represents a member of the group consisting of hydrogen andlower alkyl; R represents a member of the group consisting of hydrogen,lower alkyl, phenyl, lower alkyl phenyl, phenyl lower alkyl, and theradical in which R R and R each is a member selected from the groupconsisting of hydrogen, nitro, di(lower) alkylamino, (lower)alkanoylamino, (lower) alkanoyloxy, (lower) alkyl (including straightand branched chain saturated aliphatic groups having from 1 to 6 carbonatoms inclusive), (lower) alkoxy, sulfamyl, chloro, iodo, bromo,

fiuoro and trifiuoro-rnethyl; and the nontoxic acid addition saltsthereof (i.e., the amine salts) including the mineral acid additionsalts such as the hydrochloride, hydrobromide, hydroiodide, sulfate,sulfamate and phosphate and the organic acid addition salts such as themaleate, acetate, citrate oxalate, succinate, benzoate, tartrate,fumarate, malate, mandelate, ascorbate and the like. The ot-carbon atomof the acyl group (to which the ct-amino group is attached) may be anasymmetric carbon atom and the compounds of this invention can thereforeexist in two optically active isomeric forms [the D- and the L-diastereoisomers], as Well as in the optically inactive DL form which isa mixture of the two optically active forms; R and R taken together arecycloalkyl having from 2 to 8 carbon atoms; R represents a member of thegroup consisting of hydrogen, lower alkyl, dialkylaminoalkyl, phenyl,lower alkyl phenyl and phenyl lower alkyl; X represents a member of thegroup consisting of Among the methods for preparing novel compounds ofthe present invention is the condensation of a 2,5-oXazolidinedione witha steroid selected from the group consisting of funtumine andfuntumidine. The reaction by 3,196,169 Patented July 20, 1965 which thenew compounds of the present invention are prepared is represented asfollows:

in which the substituents shown have the values previously ascribed withrespect to compound I.

The reactants used in preparing new steroids of the present invention,generally represented by H and III above, are known to those skilled inthe art or are obtainable by processes known to the art. The preferredstart ing material represented by H, is a substituted-2,5-oXazolidinedione, where hereinafter may also be identified as anN-car-boxy amino acid anhydride. It will be noted that substitution maybe at both the 3 and 4 positions of the oxazolidinedione includingdisubstitution at the 4 po sition as shown.

These substituted oxazolidinediones may be prepared by any one ofseveral routes including (a) the carboalkoxy method, (b) the aziderearrangement or the (c) phosgenation procedure. The preferred method isthe latter in which the amino acid reactant is dissolved or suspended indioxane, phosgene is introduced into the reaction mixture and theresulting anhydride is crystallized by the addition of an agent such asbenzene.

The steroidal reactant III, namely funtumine or funtumidine, is preparedaccording to the method described in Compt. rend, Acad. Sci. 240, 3076,1958.

In the preferred method of the present invention, the substituted2,5-oxazolidinedione is reacted with funtumine or funtumidine in thepresence of an inert solvent such as dioxane, at a temperature of from 5to about 50 C. and preferably from about 15 to about 30 C. for a periodof from about /2 to about hours. At the end of the reaction period,several volumes of water are added to the reaction mixture, such as forexample two to four volumes of water, and an oily product separates.This product, the new and desired steroid, may then be worked up in aconventional'manner by drying, redissolving in solvent, reprecipitatingby the addition of water and then chilling. The'steroid separates asacolorless crystalline product.

The new steroids of the present invention have been found to possessvaluable and useful properties including specifically antimicrobialproperties. The compounds are therefore useful for this purpose and havebeen found to be particularly effective agents against B. subtilis, S.aureus and Brucella bronchiseplico.

The method of the present invention and the products obtainable therebywill be more clearly understood by reference to the following examples:

Example I A mixture of 2 grams of funtumine and 972 mg. ofN-carboxy-1-aminocyclopentanecarboxylic acid anhydride is stirred in 25ml. of dioxane at 25 C. for 24 hours. Four volumes of water are addedand an oil separates. This is removed, dried, redissolved in dioxane,reprecipitated with water, and chilled, giving 620 mg. of crystallineproduct. The dioXane-Water solution, which remains after removal of theoil, gives on chilling 250 mg. of crystalline product. The product,3ct-(l aminocyclopentanecarboxamido)5a-pregnan-20-one, shows thefollowing analysis:

Calcd for C H O N C, H, N,

Found: C, 74.7; H, 10.0; N, 6.4.

Example 11 To prepare 3 m-( 1-aminocyclopropanecarboxamido)-Salpregnan-ZO o1, N-carboxy-l-aminocyclopropanecarboxylic acid anhydrideis reacted with funtumidine according to the method of Example I.

Example 1H Following the procedure of the previous examples, N-carboxy-1-anrinocyclobutanecarboxylic acid anhydride is reacted withfuntumine to produce3a-(1-aminocyclobutanecarboxamido)-Sa-pregnan-20-one.

Following the procedure of the previous examples, if one reacts,3,4,4-trimethyl-2,5-oxazlidinedione, 4-phenyl-2,5-oxazolidinedione or4-toly1-2,S-oxazolidinedione with funtumine, one will obtain3a-(2-methyl-2-rnethyh aminopropionamido)-Stx-pregnan-20-one, 3a-(2amino- 2 phenylacetamido)-ot-pregnan -one and 3a (2-amino-Z-tolylacetamido -5 a-pregnan-20 one respectively. Similarly, byreacting 4-(2,5-dichlorophenyl)-2,5-oxazolid-inedione, 4(o-nitrophenyl)-2,5-oxazolidinedione,3-ethyl-4-isopropyl-4-methyl-2,S-oxazolidinedione or 3-phenyl-4,4-dimethyl-2,5-oxazolidinedione with funtumidine, one obtains3u-[2-am-ino-2-(2,5-dichlorophenylacetamido] 5a pregnan-ZO-ol,3oc[2-amino-2-(o-nitrophenyl) acetamido] -5tx-pregn 2111-20-01, 3 oc-Z-ethylamino- 2,3-dimethylbutyramido)-5a-pregnan-20-ol and Soc-(2-anilino-2-methylpropionarnido -5 a-pregnan-ZO-Ol res pectively.

Example IV Example V To prepare 3a-(1-am-inocycloheptanecarboxamido)-Szx-pregnan-ZO-One, N-carboxy-l-aminocycloheptanecarboxylic acidanhydride is reacted with funtumine accord- 7 ing to the method ofExample I.

Example VI A solution consisting of 1 gram of the N-carboxyanhydride ofN-phenylglycine and 1.8 grams of funtumine in of dioxane is allowed tostand at room temperature for 4 hours. The solvent is removed bysublimation. The residue of 3a-(2-anilinoacetamido)-5a-pregnan-20- oneis washed with ethyl acetate, crystallized from ethanol, and washed withacetone. M.P. 163175.

Analysis.Calcd. for C H O N C, 77.4; H, 9.3; N, 6.2. Found: C, 76.7; H,9.2; N, 6.0.

While the foregoing invention has been described with some degree ofparticularity in the specific examples set forth above, it is to beunderstood that the present invention is not to be limited thereby butrather is only to be limited by the claims appended hereto.

The invention claimed is:

1. A compound having the formula:

( f/=0 and HJIJOH 2. 3a (1 aminocyclopentanecarboxamido) 5c:pregn'an-20-one.

3. 30a (1 aminocyclopropanecarboxamid-o)-5a-pregnan-ZO-ol.

4. 30a (l aminocyclobutanecarboxamido) c pregnan-ZO-one.

5, 30 (1 aminocyclooctanecarb-oxamido) 50 pregnan-2001.

6. 3oz (2 amino-Z-phenylacetamido)-Saregn-an-ZD- one.

7. 3a (2 anilin-o 2 methylpropionamido}5a-pregnan-ZO-ol.

8. 30a (2 ethylamino-2-phenylacetamid-o) 5u-pregnan- 20-01.

9. 3w Z-anilinoacetamido -5u-pregnan-20-one.

10. The method of preparing 3a-(carboxamido)-5apregnan-ZO-one whichcomprises reacting 2,5-oxazolidinedione with funtumine in the presenceof an inert solvent and recover-ing the desired product.

11. The method of preparing 3Ct-(CarbOXa1nld0)-5QZ- pregnan-ZO-ol whichcomprises reacting 2,5-oxazolidinedione with funtumidine in the presenceof an inert solvent and recovering the desired product.

No references cited.

LEWIS GOTTS, Primary Examiner,

1. A COMPOUND HAVING THE FORMULA: